The current study was carried out to evaluate and confirm the sensitivity and specificity of S-100 protein, vimentin and HMB-45 immunohistochemical markers in diagnosis of some oral melanomas. Twelve formalin fixed paraffin- embedded specimen of some intra oral  melanomas were collected from the archives of the Clinical Pathology Department of the National Cancer Institute,  Cairo  University,  Egypt  and  the  Oral  Pathology  Department,  Faculty  of  Dental Medicine, Al- Azhar University, Cairo, Egypt between December 2005G and September 2015G. Immunohistochemical application was performed using strept-avidin-biotin peroxidase procedure. The obtained results showed a variable range of positivity of these markers in all studied cases without negative staining. These findings indicated the diagnostic significance of S-100 protein, vimentin and HMB-45 monoclonal antibodies in oral melanomas. Further studies are needed to investigate the role of these markers in metastasis and prognosis of oral melanomas.